Transdermal patch incorporating a polymer film incorporated with an active agent

ABSTRACT

Devices for the controlled release of an active agent to the skin or mucosa of a host are disclosed, which devices are laminates of a backing layer, a monolithic carrier layer of an active ingredient selected from active agent, active agent enhancers and mixtures thereof, melt-blended with a thermoplastic matrix polymer capable of controllably releasing the active ingredient, wherein the active ingredient is heat stable at the melt temperature of the matrix polymer, together with means for affixing the laminate to the skin or mucosa of the host so that the active ingredient is continuously released from the carrier layer thereto. Methods for assembling the device are also disclosed, in which a thermoplastic matrix polymer capable of controllably releasing an active ingredient is melt-blended with an active ingredient that is heat stable at the melt temperature of the matrix polymer, so that a melt-blend of the active ingredient and the thermoplastic matrix polymer is formed, which melt-blend is formed into a monolithic carrier layer, and the carrier layer is then combined with a backing layer and means for affixing the laminate to the skin or mucosa of the host so that the active ingredient is released from the carrier layer thereto.

This is a continuation of application Ser. No. 07/861,534 filed Apr. 1,1992, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to a device for the controlled release ofan active agent to a host. In particular, the present invention relatesto a transdermal delivery patch having a monolithic polymeric carrierlayer into which the active agent is melt-blended. More particularly,the present invention relates to transdermal devices for the topicalapplication of active agents such as nicotine.

Transdermal administration systems are well-known in the art. Occlusivetransdermal patches for the administration of an active agent to theskin or mucosa are described in U.S. Pat. Nos. 4,573,996 4,597,961 and4,839,174.

One type of transdermal patch is a polymer matrix or monolithic devicein which the active agent is dissolved or suspended in a polymer matrixfilm through which the active agent diffuses to the skin. Such patchesare preferred because they are relatively simpler to manufacturecompared to reservoir-type devices. Transdermal patches having amonolithic polymer film layer into which the active agent is dissolvedor suspended are disclosed by the above-mentioned U.S. Pat. No.4,839,174, as well as by U.S. Pat. Nos. 4,908,213 and 4,943,435.

U.S. Pat. Nos. 4,839,174 and 4,943,435 disclose that the active agent isincorporated into the monolithic polymer film layer by dissolving theactive agent and the polymer into a common solvent, and thensolvent-casting the film from the resulting solution. Thesolvent-casting of monolithic polymer film layers typically requires theevaporation of solvent from the cast film. This has proven to beproblematic. Because the film is employed in skin contact end useapplications, complete removal of the solvent is necessary. Solventremoval requires the application of elevated temperatures to the polymerfilm. The removal of solvent by heat-evaporation can strip the lowermolecular weight components, including the active agent, from the film,even at temperatures below which these lower molecular weight componentsvolatilize. Reducing the evaporation temperature to levels at which thelower molecular weight components are not stripped, substantiallyincreases the amount of time required for evaporation and results infilms having significant levels of residual solvent.

A transdermal patch for the delivery of an active agent having amonolithic polymer film layer into which the active agent is dissolvedor suspended without the use of solvents would be highly desirable.

SUMMARY OF THE INVENTION

This need is met by the present invention. It has now be found thatactive agents can be melt-blended with matrix polymers without firstdissolving the polymer and active agent in a common solvent.

Therefore, according to one embodiment of the present invention, adevice is provided for the controlled release of an active agent to theskin or mucosa of a host, which device is a laminate of:

(a) a monolithic carrier layer having a first surface and a secondsurface, the monolithic carrier layer being an active ingredientmelt-blended with a thermoplastic matrix polymer capable of controllablyreleasing the active ingredient, wherein the active ingredient is heatstable at the melt temperature of the matrix polymer and is selectedfrom active agents, active agent enhancers and mixtures thereof;

(b) a backing layer having an inner surface and an outer surface, theinner surface of which is affixed to the laminate so that the activeingredient cannot permeate from the second surface of the carrier layerto the outer surface of the backing layer; and

(c) means for affixing the laminate to the skin or mucosa of the host sothat the active ingredient is continuously released from the firstsurface of the carrier layer thereto.

The active ingredient is prevented from permeating the backing layer byeither utilizing an active ingredient impermeable backing layer, or bylaminating the backing layer to the carrier layer with an activeingredient impermeable adhesive layer, or both.

In preferred aspects of this embodiment, the active ingredient-permeableadhesive layer for affixing the carrier layer to the skin or mucosa ofthe host includes means for controlling the rate at which the activeingredient is released from the first surface of the carrier layer tothe skin or mucosa of the host, which rate-controlling means is affixedto the first surface of the carrier layer. In accordance with one aspectof this embodiment of the invention, the active ingredient permeableadhesive layer is capable of controlling the rate at which the activeingredient is released from the first surface of the carrier layer tothe host's skin or mucosa and functions as both the means for affixingthe laminate to the host's skin or mucosa and the means for controllingthe rate at which the active ingredient is released from the firstsurface of the carrier layer to the host's skin or mucosa.

The rate-controlling means can alternatively be provided by arate-controlling polymer layer affixed to the first surface of thecarrier layer, which rate-controlling polymer layer is capable ofcontrolling the rate at which the active ingredient is released from thefirst surface of the carrier layer to the host's skin or mucosa. Therate-controlling polymer layer can be formed from the same polymer asthe polymer matrix of the carrier layer, other compatible polymers, andeven with incompatible polymers. The rate-controlling polymer layer canbe laminated to the carrier layer with an active ingredient permeableadhesive layer. The adhesive layer may or may not control the rate atwhich the active ingredient is released from the first surface of thecarrier layer to the host's skin or mucosa. When the rate-controllingpolymer layer is formed from the same polymer or a compatible polymer,the two layers can be laminated by extrusion or coextrusion.

Regardless of how the two layers are laminated, the laminated patch isaffixed to the skin or mucosa of the host by an active ingredientpermeable adhesive layer adapted to adhere the laminate to the skin ormucosa of the host, affixed to the rate-controlling polymer layer on thesurface opposite the carrier layer. Again, this adhesive layer may ormay not control the rate at which the active ingredient is released fromthe first surface of the carrier layer to the host's skin or mucosa.

Preferably, the laminate of the invention will also include atransporting agent or enhancer to promote the penetration of the activeagent through the skin. Active agent enhancers suitable for use intransdermal delivery patches are well-known and described in U.S. Pat.No. 4,573,996, the disclosure of which is hereby incorporated herein byreference thereto. The enhancer can be melt-blended with any or all ofthe thermoplastic matrix polymer, rate-controlling polymer, if present,and active-ingredient permeable adhesives. Enhancers suitable for usewith the present invention are heat-stable at the melt temperature ofthe polymer with which they are combined.

According to another embodiment of the invention, the backing layer ofthe above-discussed embodiment extends peripherally beyond the carrierlayer about the entire periphery thereof so as to create an extendedperipheral area of the backing layer, the inner surface of whichextended peripheral area of the backing layer is laminated with anadhesive layer to adhere the laminate to the skin or mucosa of the host.In preferred embodiments, the backing layer is affixed to the secondsurface of the carrier layer by this adhesive layer, so that theadhesive layer is coextensive with the entire inner surface of thebacking layer. The adhesive layer may or may not be an active ingredientimpermeable adhesive layer, depending upon whether it is desired toprevent the active ingredient from being released radially outwardlythrough the adhesive layer coating the extended peripheral area of thebacking layer.

As with the embodiment discussed above, the laminate can also includemeans for controlling the rate at which the active ingredient isreleased from the first surface of the carrier layer. Therate-controlling means can be provided by utilizing an adhesive layercapable of controlling the rate at which the active ingredient isreleased from the first surface of the carrier layer to the host's skinor mucosa as the active ingredient permeable adhesive layer.Alternatively, the rate-controlling means can be provided by arate-controlling polymer layer affixed to the first surface of thecarrier layer, and then attached to the skin or mucosa of the host onthe surface opposite the carrier layer by an active ingredient permeableadhesive layer that may or may not control the rate at which the activeingredient is released from the first surface of the carrier layer tothe host's skin or mucosa. An active agent enhancer to promote thepenetration of the active agent through the skin can likewise bemelt-blended in the rate-controlling polymer layer or either activeingredient permeable adhesive layers.

In another embodiment of the present invention, the active ingredient inthe monolithic carrier layer is an active agent enhancer and thelaminate further includes a rate-controlling polymer layer having aninner surface and an outer surface, the rate-controlling polymer layerbeing an active agent melt-blended with a thermoplastic rate-controllingpolymer capable of controllably releasing the active agent, wherein theactive agent is heat-stable at the melt-temperature of therate-controlling polymer, and wherein the inner surface of therate-controlling polymer layer is affixed to the first surface of thecarrier layer; and an active ingredient permeable adhesive layer affixedto the outer surface of the rate-controlling polymer layer for attachingthe laminate to the skin or mucosa of the host, so that the active agentenhancer is continuously released from the first surface of the carrierlayer through the rate-controlling polymer layer and then released withthe active agent from the outer surface of the rate-controlling polymerlayer through the active agent permeable adhesive layer to the skin ormucosa of the host.

In yet another embodiment of the present invention, a plurality of theabove-described laminates are combined on a single device whereby amultiple-compartment assembly for applying a plurality of active agentsto the skin or mucosa of a host is provided. Assemblies in accordancewith this embodiment of the present invention combine a removable linerlayer including a first surface and a second surface with a bottom layerincluding a first surface and a second surface and more than one of thelaminates of the invention therebetween. The first surface of the linerlayer is a releasable surface, which is heat sealed at least at alocation between the laminates so as to physically separate thelaminates prior to removal of the removable liner layer from the bottomlayer, whereby removal of the removable liner layer eliminates the heatseal.

The laminates include all aspects of both embodiments of theabove-described laminate of a monolithic carrier layer, a backing layer,and means for affixing the laminate to the skin or mucosa of the host.The backing layer of each laminate is affixed to the first surface ofthe bottom layer, and the means for securing each laminate to the skinor mucosa of the host is affixed to the first surface of the linerlayer.

In still yet another embodiment of the present invention, a method isprovided for assembling a device for the controlled release of an activeagent to the skin or mucosa of a host, which method includes the stepsof:

(a) melt-blending a thermoplastic matrix polymer capable of controllablyreleasing an active ingredient with an active ingredient that is heatstable at the melt temperature of the matrix polymer, so that amelt-blend of the active ingredient and thermoplastic matrix polymer isformed, wherein the active ingredient is selected from active agents,active agent enhancers and mixtures thereof;

(b) forming the melt-blend into a monolithic carrier layer having afirst surface and a second surface;

(c) providing a backing layer having an inner surface and an outersurface and laminating the second surface of the carrier layer to theinner surface of the backing layer so that a laminate of the carrierlayer and backing layer is formed wherein the active ingredient cannotpermeate from the second surface of the carrier layer to the outersurface of the backing layer; and

(d) providing the laminate with an active ingredient permeable adhesivelayer for securing the laminate to the skin or mucosa of the host sothat the active ingredient is controllably released from the firstsurface of the carrier layer thereto.

In accordance with one aspect of this embodiment of the invention, thestep of providing the laminate with means for securing the laminate tothe skin or mucosa of the host includes the step of laminating an activeingredient permeable adhesive layer to the first surface of the carrierlayer. According to another aspect of this embodiment of the invention,the method further includes the step of affixing to the first surface ofthe carrier layer, means for controlling the rate at which the activeingredient is released from the first surface of the carrier layer tothe skin or mucosa of the host. The rate-controlling means may beprovided by utilizing an active ingredient permeable adhesive layercapable of controlling the rate at which the active ingredient isreleased from the first surface of the carrier layer to the host's skinor mucosa.

Alternatively, the rate-controlling means can be provided by laminatingto the first surface of the carrier layer, a rate-controlling polymerlayer capable of controlling the rate at which the active ingredient isreleased from the first surface of the carrier layer to the host's skinor mucosa. The laminating step may include the step of laminating therate-controlling polymer layer to the carrier layer with an activeingredient permeable adhesive, or, if the two polymer layers arecompatible, the laminating step includes the step of extruding, andpreferably coextruding, the rate-controlling polymer layer together withthe carrier layer. Either laminating step further includes the step ofapplying to the rate-controlling polymer layer on the surface oppositethe carrier layer, an active ingredient permeable adhesive layer adaptedto adhere the laminate to the skin or mucosa of the host. The activeingredient permeable adhesive may or may not control the rate at whichthe active ingredient is released from the first surface of the carrierlayer to the host's skin or mucosa.

According to another aspect of this embodiment of the invention, thestep of laminating the second surface of the carrier layer to the innersurface of the backing layer includes the step of laminating the secondsurface of the carrier layer to the inner surface of a backing layerhaving a greater surface area than the carrier layer so that the greatersurface area of the backing layer extends peripherally beyond thecarrier layer about the entire periphery thereof so as to create anextended peripheral area of the backing layer. The step of providing thelaminate with means for securing the carrier layer to the skin or mucosaof the host then includes the step of laminating the extended peripheralarea of the inner surface of the backing layer with an adhesive layer toadhere the laminate thereto.

Alternatively, the step of laminating the extended peripheral innersurface area of the backing layer may include the step of coating theentire inner surface of the backing layer with an adhesive layer priorto laminating the inner surface to the second surface of the carrierlayer, so that when the second surface of the carrier layer is laminatedto the inner surface of the backing layer, the layers are secured by theadhesive layer, which also extends peripherally beyond the carrier layerabout the entire periphery thereof coextensively with the extendedperipheral area of the backing layer. The adhesive layer thus bothsecures the laminate to the skin or mucosa of the host and laminates thesecond surface of the carrier layer to the inner surface of the backinglayer. The adhesive layer may or may not be an active ingredientimpermeable adhesive layer, depending upon whether or not it isdesirable for the active ingredient to permeate radially outwardlythrough the extended peripheral adhesive layer.

According to another aspect of this embodiment of the invention, anactive agent enhancer is incorporated into one or more of therate-controlling polymer or the active agent permeable adhesives,preferably by melt-blending. According to still yet another aspect ofthis embodiment, the active ingredient of the thermoplastic matrixpolymer includes an active agent enhancer, and the method furtherincludes the steps of:

(a) melt-blending a thermoplastic rate-controlling polymer capable ofcontrollably releasing an active agent that is heat stable at the melttemperature of the rate-controlling polymer so that a melt-blend of theactive agent and the thermoplastic rate-controlling polymer is formed;

(b) forming the melt-blend containing the active agent into a monolithicrate-controlling polymer layer having an inner surface and an outersurface; and

(c) laminating the inner surface of the rate-controlling polymer layerto the first surface of the carrier layer;

wherein, the step of providing the laminate with an active ingredientpermeable adhesive layer for securing the laminate to the skin or mucosaof the host includes coating the outer surface of the rate-controllingpolymer layer with an active ingredient permeable adhesive layer forsecuring the laminate to the skin or mucosa of the host, so that theactive agent enhancer is continuously released from the first surface ofthe carrier layer through the rate-controlling polymer layer and thenreleased with the active agent from the outer surface of therate-controlling polymer layer through the adhesive layer to the skin ormucosa of the host.

According to yet another aspect of this embodiment of the invention, amethod is provided for combining a plurality of the above-describedlaminates on a single device to provide a multiple-compartment assemblyfor applying a plurality of active agents to the skin or mucosa of ahost. Methods in accordance with this aspect of this embodiment of theinvention further include the steps of:

(a) providing a removable liner layer having a first surface and asecond surface, wherein the first surface of the liner layer is areleasable surface;

(b) providing a bottom layer having a first surface and a secondsurface;

(c) disposing more than one laminate for the controlled release of anactive agent to the skin or mucosa of a host between the first surfaceof the bottom layer, and the first surface of the liner layer, whereinthe backing layer of each laminate is affixed to the first surface ofthe bottom layer and the means for securing each laminate to the skin ormucosa of the host is affixed to the liner layer; and

(d) releasably heat sealing the first surface of the liner layer to thefirst surface of the bottom layer at least at a location between two ofthe laminates so as to physically separate at least two laminates priorto removal of the removable liner layer from the bottom layer, wherebyremoval of the liner layer eliminates the heat seal.

The present invention includes the discovery that thermoplastic polymerssuitable for use as carrier layers and rate-controlling layers can bemelt-blended with active agents and active agent enhancers that are heatstable at the melt temperature of the polymer. The polymer blends can beformed into carrier layers and rate-controlling polymer layers that canbe incorporated into a transdermal delivery patch from which the activeagent is controllably released. The polymer layers thus provided areobtained without first dissolving or suspending the active agent oractive agent enhancer with the polymer into a common solvent, therebyeliminating the undesirable properties resulting therefrom. Transdermaldelivery patches incorporating the polymer laminates of the presentinvention can also be prepared more economically because less loading ofthe active agent is required to obtain a desired dosage rate.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete appreciation of the invention and many other intendedadvantages can be readily attained by reference to the followingdetailed description when considered in connection with the followingdrawings, wherein:

FIG. 1 shows a side, cross-sectional view of a device according to thepresent invention.

FIGS. 2-2a show side, cross-sectional views of two other relatedembodiments of the present invention.

FIG. 3 shows a side, cross-sectional view of another embodiment of thepresent invention.

FIG. 4 shows a top, elevational, partially torn away view of anotherembodiment of the present invention showing the liner layer thereof.

FIG. 5 shows a side, cross-sectional view of the embodiment of theinvention shown in FIG. 4.

FIGS. 6-6a show side, cross-sectional views of two other relatedembodiments of the present invention.

FIG. 7 shows a top, elevational, partially torn away view of anotherembodiment of the present invention showing the liner layer thereof.

FIG. 8 shows a side, cross-sectional view of the embodiment of theinvention shown in FIG. 7.

FIG. 9 shows a side, cross-sectional view of another embodiment of thepresent invention.

FIG. 10 shows a top, elevational, partially torn away view of anotherembodiment of the present invention showing the liner layer thereof.

FIG. 11 shows a side, cross-sectional view of the embodiment of theinvention shown in FIG. 10.

FIG. 12 shows a side, cross-sectional view of another embodiment of thepresent invention.

FIG. 13 shows the nicotine release rate of two devices prepared inaccordance with separate embodiments of the present invention comparedto a control device.

FIG. 14 shows the nicotine diffusion rate of two devices prepared inaccordance with separate embodiments of the present invention comparedto a control device.

FIG. 15 shows the nicotine release rate of three devices prepared inaccordance with the invention.

It should be noted that the drawings are not necessarily to scale, butthat certain elements have been expanded to show more clearly thevarious aspects of the present invention and their advantages.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Referring to the figures, in which like numerals refer to like portionsthereof, FIG. 1 shows a device of the present invention. FIG. 1 shows across-section of the entire transdermal delivery patch device 10 of thepresent invention in its sealed configuration. The active ingredient,which may include an active agent, an active agent enhancer, or both, iscontained in a monolithic thermoplastic polymer matrix carrier layer 12.The active agent enhancer functions to promote the penetration of theactive agent through the skin. An active agent permeable skin contactadhesive layer 14 is applied to surface 15 of the carrier layer 12,providing a means for affixing the device to the skin or mucosa of thehost. Backing layer 16 is affixed by adhesive layer 18 to the surface 17of the carrier layer 12 opposite the active agent permeable adhesivelayer 14. Either the backing layer 16, or the adhesive layer 18, orboth, should be impermeable to the active ingredient so that the activeingredient does not permeate outwardly through the backing surface 10 ofthe backing layer.

Instead, the active ingredient is continuously released from the surface15 of the carrier layer 12 through the active ingredient permeable skincontact adhesive layer 14 to the skin or mucosa of the host. Protectiveliner 20 covers the active ingredient permeable skin contact adhesivelayer 14 prior to use to prevent the release of the active ingredientand to protect the skin contact adhesive layer, a pressure-sensitiveadhesive, from inactivation by ambient dust or other contaminants.

The embodiment shown in FIG. 2 differs from that in FIG. 1 only in thata rate-controlling polymer layer 22 is affixed to surface 15 of carrierlayer 12 by active ingredient permeable adhesive layer 24 to provide ameans for controlling the rate at which the active ingredient isreleased from the surface 15 of carrier layer 12 to the skin or mucosaof the host. In FIGS. 1 and 2, any or all of the adhesive layers 14 or24, or the rate-controlling polymer layer 22 may optionally include anactive agent enhancer to promote the penetration of the active agentthrough the skin.

Active ingredient permeable skin contact adhesive layer 14 is applied tothe surface of the rate-controlling polymer layer 22 opposite thecarrier layer 12 to provide a means for affixing the device to the skinor mucosa of the host. Means for controlling the rate at which theactive ingredient is released from the surface 15 of the carrier layer12 to the skin or mucosa of the host can also be provided to theembodiment of FIG. 1 by utilizing an adhesive capable of controlling therate at which the active ingredient is released from the surface 15 ofthe carrier layer 12 to the host's skin or mucosa as the activeingredient permeable skin contact adhesive layer 14.

The embodiment shown in FIG. 2a differs from that in FIG. 2 in thatrate-controlling polymer layer 22 is affixed to surface 15 of carrierlayer 12 by extrusion, or preferably, coextrusion, of the two layerstogether. Means for affixing the device to the skin or mucosa of thehost is provided by active ingredient permeable skin contact adhesivelayer 14 applied to the surface of the rate-controlling polymer layer 22opposite the carrier layer 12.

The device 110 shown in FIGS. 3 and 4 is somewhat similar to that shownin FIG. 1. Monolithic polymer matrix carrier layer 112 containing theactive ingredient has a backing layer 116 affixed to surface 117 byadhesive layer 118. Again, either or both the backing layer 116 or theadhesive layer 118 should be impermeable to the active agent. Thebacking layer 116 and the adhesive layer 118 have a sufficient surfacearea and are the shape so that, when they are attached to the carrierlayer 112, they overlap the carrier layer 112 completely. Thus, theadhesive surface adheres to the carrier layer 112 so that the adhesivelayer 118 surrounds the perimeter of the carrier layer 112 and theactive ingredient permeable skin contact adhesive layer 114 applied tosurface 115 thereof.

The active ingredient permeable adhesive layer 114 and the adhesivelayer 118 are positioned so that when the protective liner 120 isremoved, the two adhesive layers can be applied to the skin or mucosaand thus function as a means for affixing the device to the skin ormucosa of the host. The active ingredient is thus released from surface115 of carrier layer 112 through the active ingredient permeable skincontact adhesive layer 114 to provide a continuous dose of the activeingredient therethrough, but cannot permeate through the backing layer116 or when the adhesive layer 118 is active ingredient impermeable,radially outwardly therethrough.

The embodiment shown in FIG. 5 differs from that shown in FIGS. 3 and 4only in that a rate-controlling polymer layer 122 is affixed to surface115 of carrier layer 112 by active ingredient permeable adhesive layer124, thus providing a means for controlling the rate at which the activeingredient is released from the surface 115 of the carrier layer 112 tothe skin or mucosa of the host. The surface area of the rate-controllingpolymer layer 122 and the active ingredient permeable adhesive layer 124is such that the backing layer 116 and adhesive layer 118 also overlapand surround the perimeters of the rate-controlling polymer layer 122and the active ingredient permeable adhesive layer 124.

Means for controlling the rate at which the active ingredient isreleased from the surface 115 of the carrier layer 112 to the skin orthe mucosa of the host can also be provided to the embodiment of FIGS. 3and 4 by utilizing an adhesive capable of controlling the rate at whichthe active ingredient is released from the surface 115 of the carrierlayer 112 to the host's skin or mucosa as the active ingredientpermeable skin contact adhesive layer 114. The devices shown in FIGS.3-5 may optionally include an enhancer to promote the penetration of theactive ingredient through the skin. The enhancer may be included withany or all of the carrier layer 112, the rate-controlling polymer layer122, or the adhesive layers 114 or 124, whichever are present.

The embodiment shown in FIG. 6 differs from that shown in FIG. 3 and 4only in that backing layer 116 is affixed to surface 117 of monolithicpolymer matrix carrier layer 112 by extrusion and preferably coextrusionof the two layers together. Therefore, backing layer 116 is impermeableto the active ingredient so that the active ingredient does not permeateoutwardly therethrough. Means for affixing the device to the skin ormucosa of the host is provided by adhesive layer 118, which surroundsthe perimeter of the carrier layer 112 and by active ingredientpermeable skin contact adhesive layer 114, applied to surface 115 ofcarrier layer 112 and positioned with respect to adhesive layer 118 sothat when the protective liner 120 is removed, the two adhesive layerscan be applied to the skin or mucosa.

The embodiment shown in FIG. 6a differs from that shown in FIG. 6 inthat rate-controlling polymer layer 122 is affixed to surface 115 ofcarrier layer 112 by extrusion, and preferably coextrusion, of the twolayers together. Means for affixing the device to the skin or mucosa ofthe host is provided by adhesive layer 118, which surrounds theperimeter of carrier layer 112 as in FIG. 6, as well as polymer layer122, and by active ingredient permeable skin contact adhesive layer 114which is applied to surface 115 of carrier layer 112 in addition toadhesive layer 118.

The devices shown in FIGS. 6 and 6a may also optionally include anactive agent enhancer with any or all of the rate-controlling polymerlayer 122 or the adhesive layer 114, whichever are present.

The device 210 shown in FIGS. 7 and 8 represents the substitution of theembodiment of FIG. 1, with the protective liner removed, namely thecombination of the backing layer, carrier layer, and adhesive layer, forthe active agent carrying members of the device disclosed in commonlyowned U.S. Pat. No. 5,064,422, the disclosure of which is herebyincorporated herein by reference thereto. The embodiment depicted inFIGS. 7 and 8 provides a multiple-compartment assembly for applying aplurality of active agents or enhancers therefor to the skin or mucosaof a host, in which each compartment contains a monolithic thermoplasticmatrix polymer carrier layer capable of controllably releasing theactive agent or active agent enhancer. FIG. 7 shows a top, elevationalpartially torn-away view of the device in which the liner layer ispartially exposed, and FIG. 8 shows a cross-section of the entire devicein its sealed configuration.

Referring first to FIG. 8, protective liner layer 220 functions, as inthe prior embodiments, to protect the active agents as well as anypolymer or adhesive layers used in the device of this invention prior touse, and to render them transportable while not interfering with theirultimate application. Furthermore, in accordance with this invention,the liner layer 220 must be heat sealed to the bottom layer 226 in orderto not only protect the active agents, and enhancers, if present, but tomaintain them separate from each other in order to compartmentalize thedevice.

Liner layer 220 must have an inner surface 228 that is releasable withrespect to the materials or layers with which it is initially incontact, namely the active agent permeable skin contact adhesive layers214a and 214b on the active agent carrying members 230a and 230b. Theliner layer 220 therefore should include a release coating, whichrelease coating is essentially conventional.

The active agent carrying members 230a and 230b are secured on thebottom layer 226 by adhesive layers 232a and 232b. The bottom layer 226should be flexible enough to generally follow the contour of the area ofthe host where the device is to be applied. On the other hand, it shouldhave enough strength and substance so as to serve its function ofcarrying the active agent carrying members 230a and 230b withoutwrinkling. With respect to the active agent carrying members 230a and230b, in the embodiment shown in FIG. 8, they basically comprisemonolithic carrier layers 212a and 212b of the same or different activeingredients melt-blended with thermoplastic matrix polymers capable ofcontrollably releasing the active ingredients. One of monolithic carrierlayers 212a and 212b can contain an active agent enhancer for the activeagent contained in the other of the carrier layers.

As with the embodiment of FIGS. 1 and 2, active ingredient permeableskin contact adhesive layers 214a and 214b are applied to surfaces 215aand 215b of carrier layers 212a and 212b, providing a means for applyingthe carrier layers to the skin or mucosa of the host. Backing layers216a and 216b are affixed by adhesive layers 218a and 218b to surfaces217a and 217b of carrier layers 212a and 212b opposite the activeingredient permeable skin contact adhesive layers 214a and 214b. Again,either the backing layers 216a and 216b, or the adhesive layers 218a and218b, should be impermeable to the active ingredient. The active agentenhancer may be blended with either or both of the adhesive layers 214aand 214b. Protective liner 220 covers active ingredient permeable skincontact adhesive layers 214a and 214b.

The active agent carrying members 230a and 230b must be maintained incontact with bottom layer 226 by adhesive layers 232a and 232b withsufficient strength to maintain same when the active agent carryingmembers 230a and 230b are exposed or uncovered by removing liner layer220 therefrom. At the same time, this bond must be sufficiently weak inrelative terms so that bottom layer 226 will readily peel off or beremovable from the active agent carrying members 230a and 230b after theactive agent carrying members have been applied to the skin by means ofadhesive layers 214a and 214b. This is accomplished by the relationshipbetween the strength of adhesive layers 232a and 232b on the one hand,and 214a and 214b on the other hand. In this regard, the adhesive layers232a and 232b have a coefficient of adhesion which is less than thecoefficient of adhesion of the adhesive layers 214a and 214b. In thismanner, upon application of the active agent carrying members 230a and230b to the patient with the adhesive layers 214a and 214b, the activeagent carrying members will adhere to the patient and be simultaneouslyremoved from the carrier layer by way of adhesive layers 232a and 232b.

In order to produce the overall device shown in FIG. 7, the liner layer220 is brought into face-to-face contact with the bottom layer 226 withthe active agent carrying members 230a and 230b therebetween. Althoughthe liner layer 220 is secured by adhesive layers 214a and 214b coveringthe faces of active agent carrying members 230a and 230b which cover asubstantial portion of the area represented by bottom layer 226, heatseals are also provided between the liner layer 220 and the bottom layer226, at a location between the active agent carrying members 230a and230b. The location of the heat seal is shown by reference numeral 234 inFIG. 7. The heat seal is provided as a "peelable seal" between the linerlayer 220 and the bottom layer 226.

While the precise compositions of the carrier and liner layers arediscussed in more detail in this application, the nature of the facingsurfaces 228 and 236 (shown in FIG. 8) of these two layers will besignificant in creating such a "peelable seal." In this regard, itshould be noted, for example, when the two facing layer comprise innerpolyethylene layers, the creation of such a "peelable seal" is thenaccomplished in the manner described in U.S. Pat. No. 4,710,191, thedisclosure of which is incorporated herein by reference thereto.

In particular, in that patent it is disclosed that such a "peelableseal" can be created by the incorporation of a release coating on theinner surface of a layer such as liner layer 220 so as to render theheat-sealed area then created between these two layers, in this casebetween liner layer 220 and bottom layer 226, by weakening the thermalbond created therein. It is also disclosed in this patent that onealternative for achieving this result is to employ two differentmaterials as the inner layers for the liner layer 220 and the bottomlayer 226, such as polyethylene and polypropylene, etc. In such a case,the release coating would then be required on the inner surface of theliner layer 220, at least for the purposes of creating such a "peelableseal" at these locations.

In general, the purpose of the "peelable seal" is not only to separatethe device into individual compartments 237a and 237b bearing the activeagent carrying members 230a and 230b; at the same time, these "peelableseals" permit the ready separation of the liner layer 220 and thecarrier layer 226. For example, if two polyethylene layers were heatsealed together in the manner described above without a release coating,such as a silicon layer therebetween, the two layers would essentiallymelt together, and such separation would not be readily achieved. Thus,the nature of these "peelable seals" is an important feature of thepresent invention.

Referring again to FIG. 7, "peelable seals" which critically separatethe two active agent carrying members 230a and 230b are located not onlytherebetween, but extend along path 238 so as to surround both activeagent carrying member 230a and active agent carrying member 230b.Furthermore, a separate continuous heat seal 240 separate from heat seal238 surrounds the entire device including both active agent carryingmembers 230a and 230b.

In this manner, each of the active agent carrying members is isolatedprior to separation of the liner layer 220 from the bottom layer 226.The significance of this separation is that when different active agentsare to be applied in connection with active agent carrying members 230aand 230b, it will generally be necessary to carefully specify each ofthe formulations for each of the active agents. Delivery rate is acritical element in the use of any such active agents, and any prematuremigration or mixing of the active agents will alter the delivery ratewith obvious untoward consequences. Placement of the heat sealsdescribed above between the active agent carrying members 230a and 230b,however, will prevent such migration or mixing, and thus permitmaintenance of the critical and carefully devised delivery rates andpotency for each of the separate active agents therein, and at the sametime will have no adverse effect upon use of this device, i.e., thecarrier and liner layers are still readily separated when it is desiredto apply these active agents to the patient's skin.

It is further noted that the placement of such a heat seal between theactive agents hereof provides an area therebetween which could be usedfor separation of the device into separate devices. This can befacilitated by merely widening the area of this peelable heat sealbetween the active agent carrying members, for example, to provide a 1/4inch heat-seal strip therebetween. Thus, by using scissors to cutthrough such enlarged areas 238 prior to separation of the carrier layerfrom the liner layer, two separate devices can be readily provide from asingle device manufactured therein.

The embodiment shown in FIG. 9 differs from that shown in FIGS. 7 and 8only in that rate-controlling polymer layers 222a and 222b are affixedto surfaces 215a and 215b of carrier layers 212a and 212b by activeingredient permeable adhesive layers 224a and 224b to provide a meansfor controlling the rate at which the active ingredients are releasedfrom the surfaces 215a and 215b of the carrier layers 212a and 212b tothe skin or mucosa of the host. Active ingredient permeable skin contactadhesive layers 214a and 214b are applied to the surface of therate-controlling polymer layers 222a and 222b opposite the carrierlayers 212a and 212b to provide a means for affixing the devices to theskin or mucosa of the host. Active agent enhancers can also be blendedwith the polymer of the rate-controlling polymer layers 222a and 222b,and with the active ingredient permeable adhesive layers. If therate-controlling polymer and the carrier polymer are compatible, the twolayers can be extruded, and preferably, coextruded, together.

Means for controlling the rate at which the active agents are releasedfrom the surfaces 215a and 215b of carrier layers 212a and 212b to theskin or mucosa of the host can also be provided to the embodiments ofFIGS. 7 and 8 by utilizing an adhesive capable of controlling the rateat which the active agents are released from the surfaces 215a and 215bof the carrier layers 212a and 212b to the skin or mucosa as the activeagent permeable skin contact adhesive layers 214a and 214b. One or allof the active agent carrier members can include a polymer or adhesiverate-controlling means.

The embodiment shown in FIGS. 10 and 11 combine the elements of theembodiments depicted in FIGS. 3, 4, 7 and 8. Carrier layers 312a and312b containing the same or different active ingredients have backinglayers 316a and 316b affixed to surfaces 317a and 317b by adhesivelayers 318a and 318b. Again, either the backing layers 316a and 316b orthe adhesive layers 318a and 318b, or both, should be impermeable to theactive ingredient. The backing layers 316a and 316b and the adhesivelayers 318a and 318b have sufficient surface areas and are of a shape sothat, when they are attached to the carrier layers 312a and 312b, theyoverlap the carrier layers 312a and 312b completely. Thus, the adhesivesurfaces adhere to the carrier layers so that the adhesive layers 318aand 318b surround the perimeters of the carrier layers 312a and 312b andthe active ingredient permeable skin contact adhesive layers 314a and314b applied to surfaces 315a and 315b thereof.

The active ingredient permeable skin contact adhesive layers 314a and314b and the adhesive layers 318a and 318b are positioned so that whenthe protective liner 320 is removed, the adhesive layers can be appliedto the skin or mucosa, and thus function as a means for affixing thedevice to the skin or mucosa of the host. The active ingredients arethus released from the surfaces 315a and 315b of carrier layers 312a and312b through the active ingredient permeable skin contact adhesivelayers 314a and 314b to provide a continuous dose of the activeingredients therethrough, but cannot permeate through the activeingredient impermeable backing layers 316a and 316b, or, when theadhesive layers 318a and 318b are impermeable to the active ingredient,radially outwardly therethrough. As with the other depicted embodiments,active ingredient enhancers can be blended with any or all of theadhesive layers 314a and 314b.

The embodiment shown in FIG. 12 differs from that shown in FIGS. 10 and11 only in that rate-controlling polymer layers 322a and 322b areaffixed to surfaces 315a and 315b of carrier layers 312a and 312b byactive ingredient permeable adhesive layers 324a and 324b as describedabove with respect to the embodiment of FIG. 5. Active ingredientpermeable skin contact adhesive layers 314a and 314b of FIGS. 10 and 11can also be utilized as means for controlling the rate at which theactive ingredient is released from the surfaces 315a and 315b of thecarrier layers 312a and 312b to the skin or mucosa of the host for theembodiment of FIGS. 10 and 11 as described above with respect to theembodiment of FIGS. 3 and 4. Likewise, the embodiments of FIGS. 6 and 6acan be adapted to the embodiment of FIGS. 10 and 11. As with theembodiments of FIGS. 5, 6a and 9, an active agent enhancer can beblended with the polymer of the rate-controlling polymer layer.

The embodiments depicted in FIGS. 2, 5, 6a, 9 and 12 can also beformulated and assembled so that the active agent is included in therate-controlling polymer layer when an active agent enhancer is includedin the carrier layer. Thus, referring to FIG. 2, the active agent can becontained in rate-controlling polymer layer 22, with an active agentenhancer contained in the monolithic thermoplastic polymer matrixcarrier layer 12. Likewise, in the embodiments depicted in FIGS. 5 and6a, the active agent can be contained in polymer layer 122 with anactive agent enhancer contained in carrier layer 112. The active agentcan also be included with the polymer layers 222a and 222b and 322a and322b of FIGS. 9 and 12, with an active agent enhancer contained incarrier layers 212a and 212b or 312a and 312b.

The active agent can also be included in both the carrier layer andrate-controlling polymer layer. Such embodiments of the invention caninclude laminates that do not utilize an active agent enhancer, as wellas laminates that have an active agent enhancer in one or more of thecarrier layer, rate-controlling polymer layer, and active agentpermeable adhesive layers.

The present invention also includes embodiments in which active agent orthe active agent enhancer are included in layers in which they have notbeen melt-blended, which layers may also be non-polymeric. Such layersare instead prepared and assembled into the laminate by conventionalmethods using prior art materials that are well-known to those ofordinary skill in the art. Laminates in accordance with the presentinvention, however, will at the least include a carrier layer of athermoplastic matrix polymer melt-blended with an active agent, anactive agent enhancer, or both.

In addition, the present invention further includes embodiments in whichmore than one carrier layer is present or more than one rate-controllingpolymer layer is present, or both, in any order, provided that at leastone rate-controlling polymer layer, if present, is situated between acarrier layer and the skin or mucosa of the host. At least one carrierlayer is melt-blended with an active agent, active agent enhancer, orboth, otherwise the other layers may include an active agent, activeagent enhancer, or both, or may be substantially free of an active agentor active agent enhancer. The active agent or active agent enhancer maybe melt-blended with the other layers or combined with the other layersby conventional methods.

When an active agent or active agent enhancer is present in more thanone layer, the active agent or active agent enhancer of each layer maybe the same or different. The present invention also includesembodiments in which more than one active agent or active agent enhanceris included in a carrier layer or rate-controlling polymer layer.

The backing layer is preferably a thin film or sheet. In many instances,because of the area of skin to which the device is to be attached, thedevice, and therefore the backing layer, is flesh colored for cosmeticreasons. Preferably, it is a clear polyester layer, which is occlusivewith respect to the active agent or drug, but it can be dyed variouscolors, or include printed matter thereon. The backing layer normallyprovides support and a protective covering for the device.

The backing layer is preferably made of a material or combination ofmaterials that is substantially impermeable to the layer or layers withwhich it can be in contact, i.e., to the carrier layer and the activeingredient contained therein, the adhesives, etc. However, a primaryobjective is to prevent seepage of the active ingredient through thebacking layer of the device so, if the backing layer is coated on thesurface in contact with the remainder of the device with an adhesivelayer that is active ingredient impermeable, this impermeable adhesivelayer will perform this purpose even if the backing layer is not totallyimpermeable to the active ingredient. Thus, it is not necessary in allinstances that the backing layer be impermeable to the activeingredient, although in most instances it normally is, and when it isnot a layer providing this barrier function, such as an activeingredient impermeable adhesive layer, will be situated between thebacking layer and the carrier layer. By substantially impermeable, it ismeant that the other components in contact with the backing layer orcomponent under consideration will not appreciably permeate through suchlayer or component for the normal period of use and storage of thedevice.

The actual material used for the outer surface layer, i.e., referring toFIG. 1, for example, the backing layer 16, will depend on the propertiesof the materials in contact therewith. Some suitable materials include,for example, cellophane, cellulose acetate, ethyl cellulose, plasticizedvinyl acetate-vinyl chloride copolymers, ethylene-vinyl acetatecopolymer, polyethylene terephthalate, nylon, polyethylene,polypropylene, polyvinylidene chloride (e.g., SARAN), paper, cloth andaluminum foil. The material used is preferably impermeable to the activeingredient. The material which forms this backing layer may be flexibleor non-flexible. Preferably, a flexible backing layer is employed toconform to the shape of the body member to which the device is attached.

Preferably, the material which forms the backing layer, such as layer 16of FIG. 1, is a film or a composite film. The composite can be ametallized (e.g., aluminized) film or a laminate of two or more films ora combination thereof. For example, a laminate of polyethyleneterephthalate and polyethylene or a polyethylene/metallized polyethyleneterephthalate/polyethylene laminate can be employed. The preferredpolymers include polyethylene, polypropylene, polyvinyl chloride,polyethylene terephthalate and polyvinylidene chloride (SARAN). Mostparticularly, a highly preferred composition of the present inventionemploys highly occlusive layers of polyethylene terephthalate orpolyvinylidene chloride (SARAN) as a backing layer such as backingmember 16 of FIG. 1 in conjunction with a carrier layer such as carrierlayer 12 of FIG. 1 of the PEBAX materials discussed below. Thus, whilethe polyethylene terephthalate or SARAN component is highly occlusivewith respect to the materials in questions, it also is relatively stiffor hard, and therefore use of a very soft and flexible film, such as thePEBAX discussed below for a carrier layer such as carrier layer 12 ofFIG. 1, provides an excellent combination from the point of view ofcomfort and application to the user.

As described above, the backing layer is affixed to the carrier layer byan adhesive layer. For example, with respect to FIG. 1, backing layer 16is affixed to surface 17 of carrier layer 12 by adhesive layer 18. Withrespect to FIG. 3, backing layer 116 is affixed to surface 117 ofcarrier layer 112 by adhesive layer 118. In both embodiments, asdiscussed above, the adhesive layer may be active ingredient impermeableto prevent seepage of the active ingredient from the carrier layer tothe backing layer, and should be active ingredient impermeable when thebacking layer is not. In the embodiment of FIG. 3, the adhesive layer118 and the backing layer 116 extend peripherally beyond the carrierlayer 112 about the entire periphery thereof so as to create an extendedperipheral area of the backing layer 116 with the adhesive layer 118peripherally extending beyond the carrier layer 112 coextensively withthe extended peripheral area of the backing layer 116. Therefore,another purpose of the adhesive layer 118 in the embodiment of FIG. 3 isto secure the device to the skin or mucosa.

Thus, any adhesive capable of providing adhesion of the backing layer tothe carrier layer will be suitable for use with the embodiment of FIG. 1of the present invention, and any such adhesive that is also capable ofproviding adhesion to the skin or mucosa will also be suitable for usewith the embodiment of FIG. 3 of the present invention. The degree ofimpermeability of the adhesive layer to the active ingredient woulddepend upon the active ingredient and the backing layer. Preferably, theadhesive layer is a pressure-sensitive adhesive suitable for contactwith the skin or mucosa, e.g., dermatologically acceptable.

Active ingredient impermeable adhesives are typically coated onto thecarrier or backing layer in liquid form. The liquid form of theadhesives are obtained either by dissolution or suspension of theadhesive components in a liquid vehicle or emulsion or by heating athermoplastic adhesive above its melt temperature. The adhesive layer isthen either dried by evaporation of the liquid vehicle or emulsion orhardened by cooling thermoplastic material below its melt temperature.Active ingredient impermeable adhesives are thus defined as beingimpermeable to the active ingredient when the adhesive layer issubstantially dry or hardened.

Examples of suitable pressure sensitives for use in the presentinvention as the active ingredient impermeable adhesive layer includesome natural rubber and synthetic rubber adhesives and cross-linkablelaminating adhesives.

Examples of suitable natural rubber adhesives include R-1072 from B.F.Goodrich Co., No. 735 from C. L. Hathaway, and No. 5702 from Evans St.Clair. Examples of synthetic rubber adhesives include Jowatherem 270-00and Jowatherem S-3202 from Jowat Corp. and 70-9416 from National Starch.Other suitable laminating adhesives include the Dow Corning laminatingsilicone adhesives and the Lord Corporation Tycel 7900 series laminatingadhesives. The adhesives most impermeable to most active ingredients arecross-linkable laminating adhesives, which are well-known to those ofordinary skill in the art.

When utilizing pressure-sensitive adhesives, as the thickness of theadhesive layer affixing the backing layer to the carrier layerincreases, the impermeability of the adhesive layer to the activeingredient also increases. To provide active ingredient impermeabilityto the adhesive layer, the thickness of the active ingredientimpermeable adhesive layer 18 of FIG. 1 or 118 of FIG. 3 is thatthickness that provides sufficient impermeability to the activeingredient (and if necessary, to the other components of the device withwhich the impermeable adhesive layer is in contact) so that the activeingredient does not seep out of the device as explained above.Typically, to obtain active ingredient impermeability, the impermeableadhesive layer joining the backing layer to the carrier layer will havea thickness between about two and about five mils, and preferably willhave a thickness of about two mils.

Cross-linkable pressure-sensitive adhesives provide even greaterimpermeability of the adhesive layer to active agents and enhancers. Byincreasing the cross-link density of the adhesive layer, an even greaterbarrier to active agent diffusion is provided.

Returning to the structure of the devices shown in the embodiment ofFIGS. 3 and 4, the width of the adhesive layer 118 extendingperipherally beyond the carrier layer 112 about the entire peripherythereof coextensively with the backing layer 116 is that width whichprovides at least sufficient adhesion of the device to the skin ormucosa of the host in combination with the active ingredient permeableadhesive layer 114. Impermeability to the active ingredient (and, ifnecessary, to the other components of the device with which the adhesivelayer is in contact) so that the active ingredient does not seep out ofthe device, increases as the width of the layer increases.

Suitable widths will vary depending upon the active ingredient and thedegree of impermeability decreased, and range from 1/16 to 2 inches, andpreferably, 1/8 to 1 inch. In most instances, the width will be from 1/4to 1/2 inch depending on the specific use. The width need not be uniformand may vary around the perimeter of the device, e.g., to provide aspecific geometric shape or to provide a tab for removal of a protectiveliner.

The devices of the present invention may also include an activeingredient permeable adhesive layer between the carrier layer and theskin or mucosa of the host, joining the device thereto. The activeingredient permeable adhesive layer is represented by layer 14 in FIGS.1 and 2, layer 114 in FIGS. 3-6, layer 214 in FIGS. 7-9 and layer 314 inFIGS. 10-12. Certain embodiments utilize a second active ingredientpermeable adhesive layer. For example, as shown in FIG. 2, activeingredient permeable adhesive layer 24 affixes rate-controlling polymerlayer 22 to surface 15 of carrier layer 12. The device is then affixedto the skin or mucosa of the host by active ingredient permeableadhesive layer 14, which is applied to the surface of therate-controlling polymer layer 22 opposite to carrier layer 12. Such asecond active ingredient permeable adhesive layer is also represented bylayer 124 in FIG. 5, layer 224 in FIG. 9 and layer 324 in FIG. 12.

The active ingredient permeable adhesive layer that joins the device tothe skin or mucosa of the host is preferably dermatologicallyacceptable. Each active ingredient permeable adhesive layer is alsopreferably a pressure-sensitive adhesive. Any of the well-known,dermatologically acceptable, pressure-sensitive adhesives which permitdrug migration therethrough can be used in the present invention.

Some suitable permeable adhesives include acrylic or methacrylic resinssuch as polymers of alcohol esters of acrylic or methacrylic acids andalcohols such as n-butanol, isopentanol, 2-methylbutanol,1-methyl-butanol, 1-methyl-pentanol, 2-methylpentanol, 3-methylpentanol,2-ethyl-butanol, isooctanol, n-decanol, or n-dodecanol, alone orcopolymerized with ethylenically unsaturated monomers such as acrylicacid, methacrylic acid, acrylamide, methacrylamides, N-alkoxymethylacrylamides, N-alkoxymethyl methacrylamides, N-t-butyl-acrylamide,itaconic acid, vinyl acetate, N-branched alkyl maleamic acids whereinthe alkyl group has 10-24 carbon atoms, glycol diacrylates, or mixturesof these monomers; polyurethane elastomers; vinyl polymers such aspolyvinyl alcohol, polyvinyl ethers, polyvinyl pyrrolidone, andpolyvinyl acetate; urea formaldehyde resins; phenol formaldehyde resins,resorcinol formaldehyde resins; cellulose derivatives such asethylcellulose, methylcellulose, nitrocellulose, cellulose acetatebutyrate and carboxymethylcellulose; and natural gums such as guar,acacia, pectina, starch, destria, gelatin, casein, etc. Other suitablepressure-sensitive adhesives include polyisobutylene pressure sensitiveadhesives, rubber pressure-sensitive adhesives and siliconepressure-sensitive adhesives. The adhesives may also be compounded withtackifiers and stabilizers as is well-known in the art.

Adhesives that are preferred for their active agent permeability includeacrylic copolymer adhesives such as Avery Chemical Company's AS-351 HSX,preferably at a coating weight of between 25 and 35 g/m². Thispressure-sensitive adhesive is a cross-linkable polymer which provides apermanently tacky film having a total solids content of about 52%,Brookfield viscosity (LVT/Spindle No. 4/12 RPM @25° C.) of from about15,000 to 25,000 cps. at a weight per gallon of about 7.4 lbs. It canalso be diluted with hexane or toluene to a desired solids and/orviscosity range, particularly for use in conventional coating equipment.

Other such adhesives that can also be used for these purposes include anacrylic pressure-sensitive adhesive sold by National Adhesives under thedesignation DUROTAK 80-1054. This adhesive has a solids content of47.5%, a viscosity of 3,000 cps., and plasticity (Williams) of 2.9 mm.It is generally used with a solvent system including ethyl acetate,heptane, isopropyl alcohol and toluene. Another such adhesive is sold byMonsanto under the designation GELVA Multipolymer Emulsion 2484, andcomprises a stable aqueous acrylic emulsion pressure-sensitive adhesivehaving a solids content of 59% and a viscosity of 1,500 to 2,300 cps.Examples of other acrylic adhesives include Gelva 788 and 733 fromMonsanto, PS-41 from C.L.-Hathaway, Vr-0833 from H.B. Fuller, Adcot73A207A from Morton Chemical, Nos. 80-2404, 80-1054, 72-9056 and 72-9399from National Starch, Nos. E-2015, E-2067 and E-1960 from Rohm & Haas,M-6112 from Uniroyal, Inc. and Daratak 74 L from W.R. Grace. Suitablerubber adhesives include Durotak 36-6172 from National Starch andMorstik 118 from Morton Chemical. An example of a suitable siliconeadhesive is X7-4502 from Dow Corning.

The active ingredient permeable adhesive layers preferably contain someof the active ingredient when the device is placed on the skin. Thisprovides an initial active ingredient presence at the skin or mucosa andeliminates delay in absorption of the active ingredient or in topicalapplication, if that is desired. Thus, the active ingredient isimmediately available to the host. The initial active ingredientpresence may be due to the migration through the adhesive layer orlayers and, if present, rate-controlling layer, or to an amount of theactive ingredient mixed in with the active ingredient permeable adhesivelayer or layers or rate-controlling layer during manufacture. Thus,while either or both the active agent or active agent enhancer may bepresent in several of the laminate layers utilized, this may be theresult of incorporation of the ingredients in only one of the layers,followed by migration of the ingredients to other layers.

The amount of the active agent or active agent enhancer present in thepermeable adhesive layer or layers depends upon the initial drugpresence desired, e.g., for a pulse dosage. For example, U.S. Pat. No.4,031,894 discloses that 10-200 micrograms scopolamine base per cm²effective surface area is a suitable initial amount of active agent inthe permeable adhesive layer.

The width (i.e., surface area) and thickness of the permeable adhesivelayer for contact with the skin or mucosa is that width and thicknesswhich provides sufficient permeability to the active agent or activeagent enhancer and a suitable surface area to allow the dosage ratedesired to the skin or mucosa. These widths and thicknesses areconventional in the art and therefore need not be discussed in detailhere.

FIGS. 3-6 and 10-12 depict peripheral adhesive layers in direct contactand/or adjacent to the permeable adhesive layer. However, this is notnecessary and there may be a gap between the peripheral adhesive layerand the permeable adhesive layer, if desired.

The thickness and shapes of the peripheral and permeable adhesive layersin the devices of the embodiments depicted in FIGS. 3-6 and 10-12 of thepresent invention need not be the same or correspond. This is aparticular advantage to these embodiments of the invention in that thedevices can be made to adhere to specific portions of the skin or mucosaby a primary means of the peripheral adhesive layers while not affectingthe surface area of the permeable adhesive layer through which theactive ingredient passes (i.e., the shape of the device can be variedwithout varying the surface area of the permeable adhesive layer whichdetermines the amount of active agent delivered to the skin or mucosa).

With respect to the active ingredient carrier layers, such as carrierlayer 12 of FIGS. 1-2, carrier layer 112 of FIGS. 3-5, carrier layer 212of FIGS. 6-8 and carrier layer 312 of FIGS. 9-11, these layers aremonolithic polymeric active ingredient carrier layers. Thus, in essence,these monolithic active ingredient carrier layers basically comprise athermoplastic polymeric matrix which is admixed with the active agent ordrug component or active agent enhancer, or both. Unlike the monolithicpolymer matrix carrier layers of the prior art, which blend the activeagent with a matrix polymer in a common solvent and then evaporate thesolvent to form a plastic film, the carrier layers of the presentinvention are formed by blending a thermoplastic matrix polymer with theactive agent at an elevated temperature above which the polymer softensand melts, at which temperature the polymer is molten and fluid. Forpurposes of this invention, this process is defined as melt-blending.

As is readily understood by those of ordinary skill in the art, the stepof melt-blending requires the use of a thermoplastic polymer, that is,one that softens and melts when exposed to heat and then returns to itsoriginal condition when cooled. The melt-blending of the thermoplasticmatrix polymer and the active agent is discussed in greater detailbelow.

Suitable thermoplastic matrix polymers for the carrier layer,particularly for amine-containing active agents such as nicotine,include the class of elastomeric resins which are polyether blockamides, commercially designated by the trademark PEBAX. The structure ofthese polymers can be generally represented by the formula: ##STR1## inwhich PA represents a rigid polyamide segment and PE represents arelatively soft polyether segment. Another class of suitablethermoplastic matrix polymers is the thermoplastic polyurethanes. Ofthis class, the polyether polyurethanes are preferred. These includesuch commercial polyurethane compositions such as Dow Chemical Company'sPELLETHANE, including its 2363-80 AE grade thereof; K.J. Quin's Q-THANE;B.F. Goodrich's ESTANE; Mobay Chemical Company's TXIN; and others.

Suitable thermoplastic matrix polymers also include various polyesters,such as the copolymers of various cyclic polyesters including DuPont'sHYTREL, including its 4056 grade thereof, and General Electric's LOMODboth of which are copolymers of polyether prepolymers and polybutyleneterephthalate and polyisobutylene terephthalate, respectively, as wellas Eastman Chemical's PCCE. Other suitable polymers include ethylenemethacrylic and acrylic acid copolymers. For example, ethylenemethacrylic acid having the commercial designation NUCREL 699 isparticularly suitable as a thermoplastic matrix polymer for estradiol.

As will be readily understood by those of ordinary skill in the art, theactive agents suitable for use in the present invention must be heatstable at the melt temperature of the matrix polymer, and not react withthe matrix polymer at this temperature. Active agents are defined asanything to be delivered topically to or through the skin. In general,the active agents must withstand exposure to temperatures in the rangeof about 170° C. to about 200° C. for incorporation into the resinmatrix during the melt-blending process.

Active agents must have relatively good solubility in the polymermatrix, or can be solubilized in heat-resistant liquid carrierscompatible with the polymer matrix prior to the melt-blending step, suchas heat-resistant liquid plasticizers suitable for use in pharmaceuticalskin contact compositions, which are well-known to those of ordinaryskill in the art. Heat stability, for purposes of this invention, if aninsubstantial degree of thermal breakdown of the material occurs withinthe temperature range of melt-blending over the time period required formelt-blending, generally a matter of several minutes. Active agents thatare heat-sensitive but do not suffer rapid thermal degradation can beprotected from heat and made suitable for use in the present inventionby predispersion in the above-described heat resistant liquid carriers.Therefore, the definition of an active agent that is heat stable at themelt temperature of the matrix polymer includes active agentscompatibilized or heat-stabilized by dispersion in a compatibleheat-resistant liquid carrier prior to melt-blending with the matrixpolymer.

The active agents may be, for example, systemic or topical drugs.Individual active agents or mixtures thereof, if desired, can beemployed. Any drug which passes through the skin or mucosa can beemployed for internal administration in the device of the invention, solong as the drug will pass through the permeable adhesive layer orlayers present and is heat stable at the melt temperature of the matrixpolymer.

Suitable systemic drugs for administration by the devices of the presentinvention include psychoactive agents such as nicotine, caffeine,mesocarb, mefexamide, cannabinols such as THC, and the like, sedativessuch as diazepam, mepiridine, uldazepam, tybamate, metaclazepam,tetrabarbitol and the like, antidepressants such as amitryptyline,imipramine desipramine, nialamide, melitracen, isocarboxazid, and thelike, anticonvulsants such as phenobarbitol, carbamazepine,methsuximide, 2-ethyl-2-phenylmalonamide (PEMA), phenytoin and the like,steroids such as progesterone, testosterone, pregnanediol, progestin,estradiol, analbolic steroids and the like, analgesics, includingnarcotic analgesics such as codeine, morphine, analorphine, demeral andthe like, and analgesics such as acetaminophen, aspirin, alprazolam andthe like, antimicrobial agents such as sulconazole, siccanin, silversulfadiazine, bentiacide, and the like, tranquilizers such asmeprobamate and the like, antineoplastic agents such as sulfosfamide,rufocromomycin and the like, and antibiotic agents such as tetracycline,penicillin, streptozcin and the like.

The quantity of active agent present in the thermoplastic matrix polymercarrier layer is that quantity sufficient to provide a pharmaceuticallyor physiologically effective dosage rate of the active agent to a hostin need thereof. This quantity can be readily determined by those ofordinary skill in the art without undue experimentation as shown in theexamples set forth below.

In general, the active agent will be present in the thermoplastic matrixpolymer layer at levels between about 2% and about 10% by weight. Whenthe active agent is nicotine, a nicotine concentration in thethermoplastic matrix polymer layer between about 4% and about 12% byweight is suitable, and a concentration between about 8% and about 10%by weight is preferred. A nicotine concentration of about 9% by weightis most preferred.

The devices of the present invention optionally include arate-controlling polymer layer depicted as layer 22 in FIG. 2, layer 122in FIG. 5, layer 22 in FIG. 9, and layer 322 in FIG. 12. The polymerssuitable for use as the rate-controlling polymer layer are conventionalin the art and need not be discussed in detail here. Some preferredmaterials include, for example, polyethylene, polypropylene, ethylenevinyl acetate copolymer (EVA), copolyesters (e.g., HYTREL) andpolyurethanes. As will be discussed in greater detail hereinbelow, theactive agent and thermoplastic matrix polymer can be melt-blended in anextruder and then formed into the carrier layer by extrusion. Inaccordance with this aspect of the invention, the most preferredembodiments of the invention incorporating a rate-controlling polymerlayer omit the active agent permeable adhesive layer affixing therate-controlling polymer layer to the carrier layer and insteadco-extrude the two layers together.

The rate of permeation of the active agent through the rate-controllingpolymer layer depends on factors such as the affinity of the activeagent for the polymer layer, molecular size of the active agent,polymeric structure of the carrier layer and the thickness of the layer.Therefore, the appropriate rate-controlling polymeric material and itsthickness depend on the active agent used and the desired rate ofpermeation. The selection of a polymer layer and its thickness providesa means, if desired, for controlling the dosage rate to the skin ormucosa.

As noted above, an enhancer to promote the penetration of the activeagent through the skin may be included in either the carrier layer,rate-controlling polymer layer or the active agent permeable adhesivelayers. The enhancer may be incorporated into these layers by solventblending or, more preferably, by melt-blending by the same processutilized to incorporate the active agent into either the carrier layeror the rate-controlling polymer layer.

Suitable enhancers include those described in the above-cited U.S. Pat.No. 4,573,996, such as the following enhancers with a sufficiently highboiling point: monovalent, saturated and unsaturated aliphatic andcycloaliphatic alcohols having 6 to 12 carbon atoms such ascyclohexanol, lauryl alcohol and the like; aliphatic and cycloaliphatichydrocarbons such as mineral oils; cycloaliphatic and aromatic aldehydesand ketones such as cyclohexanone; N,N-di (lower alkyl) acetamides suchas N,N-diethyl acetamide, N,N-dimethyl acetamide, N-(2-hydroxyethyl)acetamide, and the like; aliphatic and cycloaliphatic esters such asisopropyl myristate and lauricidin; N,N-di (lower alkyl) sulfoxides suchas decylmethyl sulfoxide; essential oils; nitrated aliphatic andcycloaliphatic hydrocarbons such as N-methyl-2-Pyrrolidone, Azone;salicylates, polyalkylene glycol silicates; aliphatic acids such asoleic acid and lauric acid, terpenes such as cineole, surfactants suchas sodium lauryl sulfate, siloxanes such as hexamethyl siloxane;mixtures of the above materials; and the like.

When the active agent enhancer is to be melt-blended with the carrierlayer, rate-controlling polymer layer or active agent permeable adhesivelayer, the enhancer should be an active agent enhancer heat stable atthe melt temperature of the carrier polymer, rate-controlling polymer oractive agent permeable adhesive into which it is to be melt-blended. Ingeneral, the active agent enhancer should be heat stable at temperaturesbetween about 170° C. and about 200° C. As with the active agents, theactive agent enhancers can first be dispersed with a compatibleheat-resistant liquid carrier to compatibilize the enhancer with thepolymer or adhesive or to improve the heat resistance of the enhancer.

Examples of heat-resistant liquid carriers suitable for melt-blendingwith polymers or adhesives include polyethylene glycols, polypropyleneglycols, polyester and polyether polyols, epoxidized linseed oils andsimple liquid esters such as triethyl citrate, dicyclohexyl phthalate,diisodecyl adipate, and the like. The preferred liquid carrier ispolyethylene glycol.

In a preferred embodiment, the device contains a protective linerattached to the device at the surfaces to be adhered to the skin ormucosa, namely the active agent permeable adhesive layer and, ifpresent, the peripheral adhesive layer. The protective liner may be madeof the same materials suitable for use in the backing layer as discussedabove. Such material is preferably made removable or releasable from theadhesive layers by, for example, by conventional treatment with silicon,Teflon or other suitable coating on the surface thereof. The removal ofthe device from the protective liner may also be provided by mechanicaltreatment of the protective liner, e.g., by embossing the protectiveliner.

The protective liner, however, can comprise various layers, includingpaper or paper-containing layers or laminates; various thermoplastics,such as extruded polyolefins, such as polyethylene; various polyesterfilms; foil liners; other such layers, including fabric layers, coatedor laminated to various polymers, as well as extruded polyethylene,polyethylene terephthalate, various polyamides, and the like.

A particularly preferred embodiment of the protective liner of thepresent invention includes a laminate of an outer foil layer and aninner layer of plastic, such as polyethylene or the like, which isrendered releasable not only by means of a siliconized coating, butwhich also includes an embossed or roughened surface. Embossment of thissurface can be accomplished by a number of conventional methods. Ingeneral, preparation of embossed surfacing can be accomplished by theuse of male-female tooling, preferably enhanced by the application ofheat. The principle intention of this embossment process is to roughenthe surface or render it uneven so that less than the entire surfacewill be in physical contact with the corresponding adhesive layer.

The actual pattern of embossment carried out can vary, and in someinstances may involve embossment of large contiguous areas of theprotective liner. Preferably, approximately 30% of the surface of theprotective liner will thus be embossed. The particular design of theembossment, such as the production of a grainy texture or the like, is amatter of choice within the parameters discussed above. The presence ofthe embossed surface on the inner surface of the protective liner isthus extremely significant in preventing the protective liner fromsticking or adhering to the adhesive layer or layers, which would causethe liner to fail to properly separate from the adhesive layer or layerswhen it is desired to use the device of the present invention. This easeof operation is an important element in commercialization of thesedevices.

The selection of a particular protective liner will also depend uponother ultimate requirements of the particular device in question,including whether there is a desire for a transparent or opaque liner,etc.

It can thus be seen that although substantially the entire surface ofthe protective liner is in contact with the adhesive layer or layers,the seal provided to the adhesive layer or layers by the protectiveliner is "peelable" or releasable, by merely pulling apart the edge ofthe protective liner. At the same time, when this is done, the adhesivelayer or layers for contact with the skin or mucosa remain in contactwith the surface of the carrier layer and the peripherally extendedbacking area, if present, because of the coefficient of adhesion betweenthe adhesives and these layers vis-a-vis the coefficient of adhesionbetween these adhesive layers and the coated surface of the protectiveliner.

The bottom layer of the embodiments depicted in FIGS. 7-12 should beflexible enough to generally follow the contour of the area of the hostwhere the device is to be applied. On the other hand, it should haveenough strength and substance so as to serve its function of carryingthe active agent carrying members without wrinkling, etc. The actualmaterial from which the bottom layer can be produced can thereforeinclude a variety of different materials.

Some suitable materials for this layer include, for example,polyethylene, polypropylene, polyvinylidine chloride, polyethyleneterephthalate, polyesters, polyamides, and others, as well as laminatesof two or more of these layers with each other or one or more of theselayers with additional layers such as foil, paper, various fabrics,etc., but in these cases, preferably with the polymer layer on theinside, i.e., in contact with and thereby carrying the active agentcarrying members. Therefore, in a preferred aspect of these embodimentsof the invention, the bottom layer is a laminate of an outer foil layerand an inner layer of plastic, such as polyethylene or the like.

The backing layers of the active agent carrying members are disposedonto the bottom layer by one of the above-mentioned acrylic, naturalrubber or synthetic rubber pressure-sensitive adhesive. The adhesivelayer thickness is controlled in the conventional manner to insure thatthe active agent carrying members preferentially adhere to the skin ormucosa of the host over the bottom layer.

The host to which an active agent is administered by means of theinventive device may be any host on which a drug or other active agenthas the desired effect. The host may be, for example, a mammal such as ahuman being, or, for that matter, any warm-blooded or cold-bloodedanimal. The advantage of administering the active agent may betherapeutic or experimental. The device of this invention may also beused for any other advantageous purpose.

The various layers of the device of the present invention may becombined to form a laminate by methods conventional in the art. However,the present invention includes an inventive process for combining theactive agent and a thermoplastic matrix polymer by melt-blending the twocomponents, as well as an inventive process for combining polymer layerstogether by extrusion, preferably coextrusion.

The active agent and thermoplastic matrix polymer can be melt-blendedusing any art-recognized method for blending polymers with additives.Essentially, the thermoplastic matrix polymer is melt-blended with theactive agent at a temperature above the softening point of the polymerusing any conventional melt-blending apparatus including extruders,calenders, kneaders, sigma bladed mixers such as Brabender-type mixers,Banbury-type mixers and the like, preferably at a temperature betweenabout 170° C. and about 200° C.

The active agent can also be melt-blended with the rate-controllingpolymer by the above-described method. In addition, the active agentenhancer can also be melt-blended with either the thermoplastic matrixpolymer or the rate-controlling polymer by the above-described method.

The carrier layers for the devices of the present invention can beformed directly from the resulting blend or die-cut from films formedtherefrom. As such, the blends of thermoplastic matrix polymer andactive agent of the present invention can be directly extruded,calendered, compression-molded, injection-molded, thermoformed orotherwise cast, by conventional solvent-free methods well-known to thoseof ordinary skill in the art. Alternatively, the blend of active agentand thermoplastic matrix polymer can first be formed by extrusion intopellets for storage, which pellets can subsequently be formed into thecarrier layer by any of the above-mentioned forming methods.

The carrier layers of the present invention are preferably formed incompounder-extruders in which the active agent and thermoplastic matrixpolymer can be melt-blended and the resulting melt-blend extruded intothe above-mentioned pellets, or into a film from which carrier layersmay be formed, or into the actual carrier layers. The entire process iscarried out without dissolving the polymer, the active agent, or theactive agent and polymer blend in a solvent for the polymer or activeagent other than the optional compatible heat-resistant liquid carrier.

The monolithic carrier layer, once formed, can be immediately die-cutand combined on one surface with the backing layer. Alternatively, thelayers can be combined prior to die-cutting. The backing layer is eitherlaminated to the carrier layer by an adhesive layer, or by extruding thebacking layer and carrier layer together. As will be readily understoodby those of ordinary skill in the art, when the backing layer andcarrier layer are extruded together without an active agent impermeableadhesive layer, then it is critical that the backing layer be formedfrom an active agent impermeable material.

The adhesive layer providing a means for affixing the device to the skinor mucosa for the host is applied to either the carrier layer and theextruded peripheral area of the backing layer, if present. If arate-controlling polymer layer is affixed to the carrier layer, then anyadhesive layer to be affixed to the carrier layer is applied to therate-controlling polymer layer instead. Such adhesive layers can beapplied either before or after the carrier layer and backing layer arelaminated together.

Die-cutting, whenever mentioned herein, is carrier out by processeswell-known in the laminating art.

As noted above, certain embodiments include a rate-controlling polymerlayer affixed to the carrier layer on the surface to be applied to theskin or mucosa of a host. This polymer layer is either adhered to thecarrier layer by an active agent permeable adhesive layer, or, thislayer can also be extruded with the carrier layer, alone, or with thebacking layer. As is well understood to those of ordinary skill in thepolymer forming art, layers of the same or different polymers areconventionally extruded together. Two or more of the carrier layer,backing layer and rate-controlling polymer layer can be coextrudedtogether in a single step. When all three layers are coextruded, theonly adhesive layer required will adhere the rate-controlling polymerlayer, and thus the laminate, to the skin or mucosa of the host.

The device, once formed, may be kept sealed in an air-tight pouch priorto use. The device of the present invention is used in the same manneras those devices which are conventional in the prior art. In mostinstances, the releasable protective liner attached to the skin-sidesurface of the adhesive layer or layers of the device for contact withthe skin or mucosa of the host is removed and such surface of theadhesive layer or layers is applied to the desired area of the skin ormucosa.

The following non-limiting examples set forth hereinbelow illustratecertain aspects of the invention, but are not meant in any way torestrict the effective scope of the invention. All parts and percentagesare by weight unless otherwise noted, and all temperatures are indegrees Celsius.

EXAMPLES Example 1

A mixture of 5.5 lb. of PEBAX-4033 polyetherpolyamide block copolymerresin was melt-blended with 227 g of nicotine in a Werner-PfleidererModel ZSK-30 30 mm twin screw compounder extruder. The two componentswere melt-blended at 170° C. and extruded into pellets. The nicotinecontent of the pellets was determined to be 8.20% by methanolextraction.

A film having an average thickness of 9.6 mil was pressed out of thepellets using a Carver laboratory press at a pressure of 1500 psi and amelt temperature of 350° F. 10 cm discs were die-cut from thepressed-out film having an average thickness of 9.6 mil and an averageweight of 242.3 mg.

Mono Discs were formed from the PEBAX-nicotine discs by affixing the 10cm² PEBAX discs to 10 cm² SARAN/HYTREL occlusive film discs 1.5 milthick with a 3.1 mil thick layer of Gelva 737 (Monsanto) acrylicpressure-sensitive adhesive. The opposite side of the disc was thencoated with a 1.7 mil thick layer of Gelva 737, which is a skin contactpressure-sensitive adhesive. The adhesive was then covered with arelease liner.

Double discs were also prepared as in FIGS. 3-4 utilizing a 20 cm², 1.5mil thick SARAN/HYTREL occlusive film as the backing layer 116, whichwas coated with a 3.1 mil thick layer of Gelva 737 acrylicpressure-sensitive adhesive, serving as the adhesive layer 118. The 10cm² PEBAX-nicotine disc served as the carrier layer 112. A 1.7 mil thickcoating of Gelva 737 pressure-sensitive adhesive served as the adhesivelayer 114. The skin contact adhesive was also protected with a releaseliner.

The nicotine content of these two types of patches was determined bymethanol extraction, with a NICOTINELL-TTS 20 (Ciba-Geigy) patchmeasured as a control. The NICOTINELL-TTS 20 patch is a laminate of 0.5mil of an occlusive film to a 6.0 mil non-woven cellulose layer with a4.5 mil acrylic pressure-sensitive adhesive. The non-woven celluloselayer is impregnated with nicotine. The opposite side of the celluloselayer is then coated with an 8.5 mil layer of a cross-linked acrylicskin contact pressure-sensitive adhesive, which is then covered with arelease liner. The three patches were extracted in 40 mL methanol for 16hours at room temperature and subsequently sonicated for 1/2 hour.Sonication is an action of ultra sound waves which generate high energyvibrations within a polar media such as water or methanol causing arapid dissolution and disintegration of submerged materials.

Both the mono disc and double disc patches were determined by HighPerformance Liquid Chromatography (HPLC) to contain 18 mg of nicotineper 10 cm² patch. By the same test, the NICOTINELL-TTS 20 patch wasdetermined to have a nicotine content of 35 mg.

The nicotine release of the three patches was tested by a standardizedtesting method. Each of the three patches was attached to the bottom ofa 250 mL beaker by means of double-sided adhesive tape in such a mannerthat the skin-contact side of the patch was facing upwards. 100 mL ofwater at room temperature was added to each beaker, the tops were sealedand the test starting time was recorded. At 2 hours, 4 hours, 6 hoursand 24 hours, the water in the beakers was stirred for 2 minutes and a2-3 mL sample was withdrawn from each beaker for analysis by HPLC. Theconcentration of the nicotine of the water was then determined usingcalibration standards, thus providing the drug release kinetics. Theresults are presented in Table I and FIG. 13. The results demonstratethat both the mono disc 1 and double disc 2 deliver nicotinetransdermally at the same rate, and at a slightly greater rate than thecontrol 3.

                  TABLE I                                                         ______________________________________                                                                     Nicotinell                                              Mono Disc Double Disc TTS 20                                           ______________________________________                                        Patch Size                                                                    Inner Disc                                                                             10      cm.sup.2                                                                              10    cm.sup.2                                                                            --                                       Outer Disc                                                                             --          20      cm.sup.2                                                                            20    cm.sup.2                             Nicotine 18.0    mg      18.0  mg    35.0  mg                                 Content                                                                       Release Rate -- (mg/cm.sup.2)                                                  6 hrs.  0.78        0.78        0.53                                         24 hrs.  1.53        1.53        0.95                                         Diffusion Rate -- (mg/cm.sup.2)                                                6 hrs.  2.01        2.01        1.56                                         24 hrs.  3.16        3.16        2.78                                         ______________________________________                                    

The diffusion kinetics of nicotine from the three types of patchesthrough a skin substitute was also measured using the Franz DiffusionCell Method. In this method, an excised human or animal skin wasoverlayed with a transdermal patch in such a way that the adhesive sideof the patch was in contact with the skin. This patch/skin laminationwas then mounted onto a Franz Diffusion Cell on top of the lower, orreceiving, chamber of the cell, which was filled with isotonic saline atpH 7.4. This saline solution contacts the skin at the top of thechamber. The temperature of the isotonic solution was maintained at 37°C. by thermostatically controlled water circulation through a jacketsurrounding the receiving chamber. Homogeneous distribution oftemperature was achieved by a small magnetic stirrer. Thus, the skin washeld under conditions approximating the living state.

At 2 hours, 4 hours, 6 hours and 24 hours, 1 to 2 mL of the salinesolution was withdrawn from the receiving chamber and analyzed by HPLC.The drug concentration in the saline solution sample was calculatedusing calibration standards and the drug permeation kinetic profilethrough the skin was thus obtained.

The skin substitute utilized in Example 1 was porcine xenograft (E-ZDerm, from Bioplasty, Inc., St. Paul, Minn.). The results are presentedin Table I and FIG. 14. Again, the test results demonstrate that boththe mono disc and double disc deliver nicotine transdermally atvirtually the identical rate 4, and at a slightly greater rate than thecontrol 5.

Example 2

Mono disc patches containing rate-controlling polymer layers wereprepared as in FIG. 2 by affixing the 10 cm² PEBAX discs of Example 1 toa 1.5 mil SARAN/HYTREL occlusive film with a 1.8 mil layer of Gelva 737acrylic pressure-sensitive adhesive. The opposite side of the PEBAX discwas then coated with a 1.8 mil layer of Gelva 737 adhesive to which a1.0 mil rate-controlling polymer layer was laminated. A 1.8 mil layer ofGelva 737 was then added to the opposite side of the rate-controllingpolymer layer, which adhesive layer was then covered with a releaseliner. Patches were prepared with three different rate-controllingpolymeric layers: Hytrel 4056, ethylene vinyl acetate (EVA) and SURLYN1702 ionomer resin. A first control patch was prepared without arate-controlling polymeric layer. A NICOTINELL-TTS 20 patch was utilizedas a second control. The five patches were then analyzed for theirrelease rates of nicotine by the test described in Example 1 in whicheach patch was attached to the bottom of a 250 mL beaker by double-sidedadhesive tape with the skin-contact side of the patch facing upwards.The test and results are presented in Table II and FIG. 15. FIG. 15depicts the release rate with time for patches with rate-controllingpolymer layers of SURLYN 1702 7, EVA 8 and HYTREL 4056 9, compared tothe NICOTINELL-TTS 20 control 11.

                  TABLE II                                                        ______________________________________                                        Type of Rate     Release Rate                                                 Controlling Polymeric Layer                                                                    mg/cm.sup.2 After 24 Hours                                   ______________________________________                                        None             1.53                                                         1 mil Hytrel 4056                                                                              0.87                                                         1 mil EVA        0.42                                                         1 mil SURLYN 1702                                                                              0.00                                                         NICOTINELL-TTS 20                                                                              0.95                                                         ______________________________________                                    

The most permeable rate-controlling polymer layer was the Hytrel 4056.The patch containing this rate-controlling polymer layer demonstrated arelease rate comparable to the NICOTINELL-TTS 20 patch. The release ratefor the patch with the Hytrel 4056 layer at 24 hours was 0.87 mg/cm²,compared to 0.95 mg/cm² for NICOTINELL-TTS 20. These values may beconsidered to be the same within experimental error. EVA showed theslowest permeability, while Surlyn proved to be a very good barrier fornicotine.

In summary, this example demonstrates that a mono disc patch with arate-controlling polymeric layer of 1.0 mil Hytrel 4056 deliversnicotine transdermally at practically the same rate as NICOTINELL-TTS20.

Example 3

Mono disc patches containing different skin contact pressure-sensitiveadhesives were prepared as in FIG. 1 by affixing the 10 cm² PEBAX discof Example 1 to a 1.5 mil 10 cm² SARAN/HYTREL occlusive film disc with a1.8 mil layer of Gelva 737. The opposite side of the PEBAX disc was thencoated with a 1.8 mil layer of skin contact pressure-sensitive adhesiveand covered with release liner. Patches were prepared with threedifferent skin contact pressure-sensitive adhesives: Gelva 737, Durotak36-6172 (National Starch and Chemical, Bridgewater, N.J.) and Morstik118 (Morton International, Chicago, Ill.). The patches were thenanalyzed for their release rate of nicotine by the test described inExamples 1 and 2 in which each patch was attached to the bottom of a 250mL beaker by double-sided adhesive tape with the skin-contact side ofthe patch facing upwards. The release kinetics results are depicted inTable III.

                  TABLE III                                                       ______________________________________                                        Skin Contact     Release Rate                                                 Pressure-Sensitive Adhesive                                                                    After 24 Hours mg/cm.sup.2                                   ______________________________________                                        NICOTINELL-TTS 20                                                                              0.95                                                         Gelva 737        1.53                                                         Durotak 36-6172  1.40                                                         Morstik-118      1.13                                                         ______________________________________                                    

The results in Table III illustrate that the release rate of nicotinecan be controlled by the selection of adhesive. With Morstik 118, therelease kinetics are virtually the same as for NICOTINELL-TTS 20. Thus,it has been demonstrated that the skin contact pressure-sensitiveadhesive controls the release rate of nicotine from the carrier polymermatrix.

Example 4

PEBAX-nicotine pellets were prepared as in Example 1 and then castextruded into an 8.0 mil film on a carrier web. A 1.0 mil HYTREL 4033film was cast extruded and heat laminated to the PEBAX film. A 1.0 milMYLAR polyester occlusive layer was adhesive laminated to the oppositesurface of the PEBAX film using 1.0 mil of GELVA 737 bonding adhesive. A1.8 mil film of GELVA 737 skin contact adhesive was then transfer coatedto the underside of the rate-controlling polymer layer. The filmlaminate was then die-cut into 20 cm² mono discs. Comparative analytictesting was then performed on these discs and reference patches from twodifferent manufacturers. The reference patches were 10 cm² and 15 cm²NICODERM™ Nicotine patches (Marion Merrell Dow) and 10 cm² and 30 cm²HABITROL™ Nicotine patches (Basel Pharmaceuticals Division ofCiba-Geigy).

The nicotine content of the patches was determined by extracting thepatches in HPLC grade methanol. The nicotine content was thenquantitatively determined by analyzing the extracts using HPLC. Thedissolution kinetics analysis was performed according to United StatesPharmacopeia, Method USP XXII (724) No. 3, Paddle over Disc. Thenicotine was quantified by HPLC. Franz Diffusion Cell Tests wereperformed at 37° C. using excised skin from a hairless guinea pig.Extracts were sampled after 24 hours and quantified on HPLC. The purityof the nicotine contained in the extruded PEBAX film was determined byextraction in HPLC grade methanol and acetonitrile. Three differentanalytical methods were used to determine if any impurities ordegradation products were present in the PEBAX film, gas chromatography,HPLC and UV-VIS spectrophotometry. The GC and HPLC chromatograms werecompared to GC and HPLC chromatograms of 99% pure, free base nicotinefor the detection of additional peaks. The absorption bands of theUV-VIS spectra were also compared between the extract and 99% pure, freebase nicotine.

The PEBAX nicotine patches were packaged in pouches classified asCategory A according to USP standards, USP XXII (671). Two storageconditions were chosen, ambient temperature and relative humidity, and40° C. and ambient relative humidity. The stability program wasestablished for 26 weeks with interval testing performed at 4, 8, 13 and26 week intervals. At each time interval, the dissolution kinetics andnicotine content procedures are performed.

The results of the nicotine content, dissolution testing, and FranzDiffusion Cell Testing are presented in Table IV. The PEBAX purityresults are shown in Table V. With respect to the stability study of thePEBAX nicotine patch, as of Jan. 20, 1992, 4 and 8 week interval testinghas been performed, and the results are shown in Table VI.

                  TABLE IV                                                        ______________________________________                                        CONTENT OF NICOTINE                                                           Patch Description                                                                            Patch Area                                                                              Nicotine                                             ______________________________________                                        Mono Disc      20 cm.sup.2                                                                             39.5 mg                                              NICODERM ™ Patch                                                                          15 cm.sup.2                                                                             78.0 mg                                              HABITROL ™ Patch                                                                          20 cm.sup.2                                                                             35.0 mg                                              ______________________________________                                        DISSOLUTION RESULTS                                                           Patch Description  6 Hours    24 Hours                                        ______________________________________                                        Mono Disc          1.47 mg/cm.sup.2                                                                         2.09 mg/cm.sup.2                                NICODERM ™ (10 cm.sup.2 Fragment)                                                             0.97 mg/cm.sup.2                                                                         1.60 mg/cm.sup.2                                HABITROL ™ (10 cm.sup.2 Fragment)                                                             1.71 mg/cm.sup.2                                                                         3.07 mg/cm.sup.2                                ______________________________________                                        FRANZ DIFFUSION CELL RESULTS                                                              Nicotine In-Vitro Diffusion Rate                                              After 24 Hours                                                    Patch Description                                                                           mg/Exposed Area                                                                           mg/cm.sup.2                                         ______________________________________                                        Mono Disc     2.2         0.58                                                NICODERM ™ 3.1         0.82                                                HABITROL ™ 2.2         0.59                                                ______________________________________                                    

                  TABLE V                                                         ______________________________________                                        PURITY OF NICOTINE EXTRUDED FILM                                                               Impurity/Degredation                                         Analytical Method                                                                              Peaks Detected                                               ______________________________________                                        Gas Chromatography                                                                             None                                                         High Performance None                                                         Liquid Chromatography                                                         UV-VIS Spectrophotometry                                                                       None                                                         ______________________________________                                    

                  TABLE VI                                                        ______________________________________                                        STABILITY STUDY RESULTS                                                       ANAL-            ROOM                                                         YTICAL   START   TEMPERATURE   40° CELSIUS                             TEST     VALUE   4 WEEKS  8 WEEKS                                                                              4 WEEKS                                                                              8 WEEKS                               ______________________________________                                        Dissolution                                                                            2.09    2.05     2.02   2.07   1.88                                  Kinetics For                                                                  24 Hours                                                                      [mg/cm.sup.2 ]                                                                Nicotine 39.5    39.3     37.7   39.4   35.8                                  Content                                                                       Per Patch                                                                     [mg]                                                                          ______________________________________                                    

The 15 cm² NICODERM™ patch and the 20 cm² HABITROL™ patch have the samepublished in vivo delivery rate of nicotine, 14 mg/day, yet the nicotinecontent is very different. Delivery rate therefore does not directlyrelate to nicotine content. Consequently, the in vivo delivery rate ofthe PEBAX patch cannot be calculated based solely on its nicotinecontent.

The exposed area of the patch for both dissolution testing and FranzDiffusion Cell Testing was die-cut from the center of NICODERM™ andHABITROL™ patches. The release rate in water shows significantdifferences among the three patches. Because the in vivo delivery rateis known to be 14 mg/day for both the NICODERM™ and HABITROL™ patches,this shows that no correlation may be drawn between water release rateand the in vivo delivery rate for the PEBAX nicotine patch.

With respect to the Franz Diffusion Cell results, the PEBAX nicotinepatch shows identical percutaneous absorption through hairless guineapig skin compared to the NICODERM™ and HABITROL™ patches. BecauseNICODERM™ and HABITROL™ patches exhibit identical in vivo deliveryrates, one can safely project the in vivo delivery rate of the PEBAXpatch. Calculated delivery rates for the three common standard sizes ofnicotine patches are shown in Table VII.

                  TABLE VII                                                       ______________________________________                                        CALCULATED NICOTINE IN-VITRO DIFFUSION                                        RATES FOR VARIOUS PATCH SIZES                                                           IN-VIVO      PATCH   IN-VITRO                                       PATCH     DELIVERY RATE                                                                              SIZE    DELIVERY RATE                                  DESCRIPTION                                                                             [MG/DAY]     [CM.sup.2 ]                                                                           [MG/DAY]                                       ______________________________________                                        Mono Disc  7 Projected 10      6.0                                                      14 Projected 20      12.0                                                     21 Projected 30      18.0                                           NICODERM ™                                                                            7 Known      7      6.0                                                      14 Known     15      12.0                                                     21 Known     22      18.0                                           HABITROL ™                                                                            7 Known     10      6.0                                                      14 Known     20      12.0                                                     21 Known     30      18.0                                           ______________________________________                                    

With reference to the purity results of Table V, these resultsdemonstrate that the extrusion process does not in any way degrade thenicotine or introduce impurities into the extruded PEBAX-nicotine matrixfilm. The stability study results of Table VI prove that thePEBAX-nicotine transdermal system is stable over time in varying storageconditions.

The PEBAX-nicotine transdermal system of the present invention clearlyshows very similar release characteristics to other reference nicotinetransdermal systems. Specifically, the in vitro release characteristicthrough guinea pig skin of the PEBAX-nicotine patch matches those of thereference patches very closely. The innovative physical structure andsimplified construction of the PEBAX-nicotine transdermal system makesthis system stand out from the other commercial nicotine patches byachieving substantial savings in manufacturing costs.

As will be readily appreciated, numerous variations and combinations ofthe features set forth above can be utilized without departing from thepresent invention as set forth in the claims. Such variations are notregarded as a departure from the spirit and scope of the invention, andall such modifications are intended to be included within the scope ofthe following claims.

What is claimed is:
 1. A device for the controlled release of an activeagent to the skin or mucosa of a host, said device comprising a laminateof:(a) A monolithic polymer film carrier layer having a first surfaceand a second surface, said carrier layer comprising an active ingredientmelt-blended with a thermoplastic matrix polymer capable of controllablyreleasing said active ingredient without first dissolving or suspendingsaid polymer or active ingredient in a solvent therefor, so that saidcarrier layer is substantially free of residual solvent, wherein saidpolymer has a melt temperature between about 170° C. and about 200° C.and is selected from the group consisting of polyether block amides,ethylene methacrylic acid copolymers, ethylene acrylic acid copolymers,copolymers of polyether prepolymers with polybutylene terephthalate andpolyisobutylene terephthalate and polyether polyurethanes, and saidactive ingredient is heat stable at said melt temperature of said matrixpolymer, and is selected from the group consisting of active agents,active agent enhancers, and mixtures thereof; (b) An activeingredient-impermeable backing layer having an inner surface and anouter surface, wherein said second surface of said carrier layer andsaid inner surface of said backing layer are extruded together withoutan adhesive layer therebetween, so that said active ingredient cannotpermeate from said second surface of said carrier layer through saidouter surface of said backing layer; and (c) Pressure-sensitive adhesivemeans for affixing said laminate to said skin or mucosa of said host sothat said active ingredient is capable of being continuously releasedfrom said first surface of said carrier layer thereto.
 2. The laminateof claim 1, wherein said means for affixing said laminate to said skinor mucosa of said host comprises an active ingredient permeable adhesivelayer affixed to said first surface of said carrier layer.
 3. Thelaminate of claim 1, further comprising means for controlling the rateat which said active ingredient is released from said first surface ofsaid carrier layer to said skin or mucosa of said host.
 4. The laminateof claim 3, wherein said rate-controlling means comprises an activeingredient permeable adhesive layer affixed to said first surface ofsaid carrier layer and adapted to adhere said first surface of saidcarrier layer to said skin or mucosa of said host, wherein said adhesivelayer is capable of controlling the rate at which said active ingredientis released from said first surface of said carrier layer to said skinor mucosa.
 5. The laminate of claim 3, wherein said rate-controllingmeans comprises a rate-controlling polymer layer affixed to said firstsurface of said carrier layer and adhered to said skin or mucosa of saidhost by an active ingredient permeable adhesive layer affixed to saidrate-controlling polymer layer on the surface opposite said carrierlayer.
 6. The laminate of claim 1, wherein said backing layer extendsperipherally beyond said carrier layer about the entire peripherythereof, thereby defining an extended peripheral area of said backinglayer, and said means for affixing said laminate to said skin or mucosaof said host comprises an adhesive layer adapted to adhere said extendedperipheral area of said backing layer to said host's skin or mucosa. 7.The laminate of claim 6, wherein said means for affixing said laminateto said skin or mucosa of said host further comprises an activeingredient permeable adhesive layer affixed to said first surface ofsaid carrier layer.
 8. The laminate of claim 6, further comprising meansfor controlling the rate at which said active ingredient is releasedfrom said first surface of said carrier layer to said skin or mucosa ofsaid host.
 9. The laminate of claim 1, wherein said backing layercomprises one or more layers of an occlusive material, wherein eachlayer of material is independently selected from the group consisting ofcellophane, cellulose acetate, ethyl cellulose, plasticized vinylacetate-vinyl chloride copolymers, ethylene-vinyl acetate copolymer,polyethylene terephthalate, nylon, polyethylene, polypropylene,polyvinylidene chloride, paper, cloth and aluminum foil.
 10. Thelaminate of claim 9, wherein each layer of material is independentlyselected from the group consisting of polyethylene, polypropylene,polyvinyl chloride, polyvinylidene chloride and polyethyleneterephthalate.
 11. The laminate of claim 10, wherein each layer ofmaterial is independently selected from the group consisting ofpolyethylene terephthalate and polyvinylidene chloride.
 12. The laminateof claim 2, wherein said adhesive layer comprises a pressure-sensitiveadhesive material selected from the group consisting of polyisobutyleneadhesives, silicon adhesives, acrylic adhesives and synthetic rubberadhesives.
 13. The laminate of claim 12, wherein said acrylicpressure-sensitive adhesive comprises a polymer of alcohol esters ofacrylic or methacrylic acid.
 14. The laminate of claim 13, wherein saidesters of polyacrylic acid and polymethacrylic acid are esters ofalcohols selected from the group consisting of N-butanol, isopentanol,2-methylbutanol, 1-methylbutanol, 1-methylpentanol, 2-methylpentanol,3-methylpentanol, 2-ethylbutanol, isooctanol, n-decanol and n-dodecanol.15. The laminate of claim 14, wherein said esters of polyacrylic acidand polymethacrylic acid are copolymerized with one or moreethylenically unsaturated monomers selected from the group consisting ofacrylic acid, methacrylic acid, acrylamide, methacrylamide,N-alkoxymethyl acrylamide, N-alkoxymethyl methacrylamide,N-t-butylacrylamide, itaconic acid, vinyl acetate, N-branched alkylmalemic acid with alkyl groups from 10 to 24 carbon atoms and glycoldiacrylates.
 16. The laminate of claim 2, wherein said adhesive layercomprises a dermatologically acceptable pressure-sensitive adhesiveselected from the group consisting of polyurethane elastomers, polyvinylalcohol, polyvinyl ethers, polyvinyl pyrrolidone, polyvinyl acetate,urea formaldehyde resins, phenol formaldehyde resins, resorcinolformaldehyde resins, ethyl cellulose, methyl cellulose, nitrocellulose,cellulose acetate butyrate, carboxymethyl cellulose, guar gum, acaciagum, pectina gum, destria gum, gelatin and casein.
 17. The laminate ofclaim 1, wherein said active ingredient comprises an active agentselected from the group consisting of psychoactive agents selected fromthe group consisting of nicotine, caffeine, mesocarb, mefexamide andcannabinols; sedatives selected from the group consisting of diazepam,mepiridine, uldazepam, tybamate, metaclazepam and tetrabarbitol;antidepressants selected from the group consisting of amitryptyline,imipramine, desipramine, nialamide, melitracen and isocarboxazid;anticonvulsants selected from the group consisting of phenobarbitol,carbamazepine, methsuximide, 2-ethyl-2-phenylmalonamide and phenytoin;steroids selected from the group consisting of progesterone,testosterone, pregnanediol, progestin and estradiol; narcotic analgesicsselected from the group consisting of codeine, morphine, analorphine anddemeral; analgesies selected from the group consisting of acetaminophen,aspirin and alprazolam; antimicrobial agents selected from the groupconsisting of sulconazole, siccamin, silver sulfadiazene and bentiacide,tranquilizers; antineoplastic agents selected from the group consistingof sulfosfamide and rufocromomycin; and antibiotic agents selected fromthe group consisting of tetracycline, penicillin and streptozocin. 18.The laminate of claim 17, wherein said active agent comprises nicotine.19. The laminate of claim 5, wherein said rate-controlling polymer layera material selected from the group consisting of polypropylene,polyethylene, ethylene vinyl acetate, polyether polyurethanes, polyetherblock amides, ethylene methacrylic acid copolymers, ethylene acrylicacid copolymers and copolymers of polyether and polybutyleneterephthalate and polyisobutylene terephthalate.
 20. The laminate ofclaim 5, wherein one or more of said rate-controlling polymer layer andeither of said active agent permeable adhesive layers further comprisean active agent enhancer.
 21. The laminate of claim 20, wherein saidactive agent enhancer is melt-blended with one or more of saidrate-controlling polymer layer and either of said active agent permeableadhesive layers and is heat-stable at a melt temperature between bout170° C. and about 200° C.
 22. The laminate of claim 21, wherein saidactive agent enhancer is selected from the group consisting ofmonovalent, saturated and unsaturated aliphatic and cycloaliphaticalcohols having 6 to 12 carbon atoms, aliphatic and cycloaliphatichydrocarbons, cycloaliphatic and aromatic aldehydes and ketones,N,N-dialkyl acetamides, aliphatic and cycloaliphatic esters, N,N-dialkylsulfoxides, essential oils, nitrated aliphatic and cycloaliphatichydrocarbons, salicylates, polyalkylene glycol silicates, aliphaticacids, terpenes, surfactants and siloxanes.
 23. The laminate of claim 1,wherein said backing layer and said carrier layer are coextrudedtogether.